The goal of the proposed work is to investigate the effect of polymorphic variation in the genes encoding brain-derived neurotrophic growth factor (BDNF) and a serotonin transporter promoter protein (locus, SLC6A4; variant, 5-HTTLPR) on hippocampal volume in bipolar disorder (BD). BD affects approximately 1% of individuals and is associated with significant suffering and a high suicide rate. Treatments are often ineffective, as understanding of the neuropathophysiology of the disorder is limited by a paucity of study. The identification of a neural endophenotype associated with a specific biochemical mechanism (and a specific genotype) could provide key information to aid development of earlier detection and targeted treatment strategies. Effects of genetic variation at the BDNF and SLC6A4 5-HTTLPR loci on the development of abnormalities in hippocampal volume in BD are implicated by associations to BD of polymorphisms in genes encoding BDNF and the SLC6A4, and by major effects of variations in BDNF and serotonin on hippocampal development. Reciprocal regulatory effects between BDNF and serotonin in their modulation of hippocampal development suggest interaction between genetic variation at the two loci on the development of hippocampal abnormalities in BD. Our pilot data provide evidence to support greater reductions in hippocampal volumes in BD in association with the BDNF Met allele, as compared to reductions that were also detected in association with this genotype in healthy individuals. We also detected decreased hippocampal volume in a BD subgroup who carry the low activity 5-HTTLPR "short" allele as compared to individuals with the "long"/"long" genotype. Moreover, our pilot data suggest interactions between the two genotypes in their influences on hippocampal volumes in BD. The proposed work, by a new investigator, employs structural magnetic resonance imaging to study influences of these genotypes on hippocampal volume in a BD group (N=100) and a healthy control group (N=100). To the best of our knowledge this is the first integrated neuroimaging and genetic study of modification of regional brain abnormalities in BD by genetic variations.